Introduction: Mutations in the thyroid hormone (TH) transporter MCT8 result in MCT8 deficiency, which is characterized by severe intellectual and motor disability and high serum T3 concentrations inducing thyrotoxicity in peripheral tissues. At present, no effective treatment is available, although preclinical studies suggest that the T3 analog Triac is a promising candidate to i) normalize serum T3 levels and thus alleviate the thyrotoxicosis and ii) restore TH signaling in the brain.
Objective: To study the effect of Triac on serum T3 concentrations and signs of thyrotoxicosis in patients with MCT8 deficiency.
Methods: We conduct a world-wide prospective interventional trial in which 46 patients with MCT8 deficiency receive Triac treatment for 1 year. The primary end-point is the reduction of serum T3 concentrations, and secondary end-points include normalization of heart rate (HR), improvement of body weight (BW) and serum parameters that reflect TH action in peripheral tissues. The neuro(psycho)logical phenotype is assessed before and after 1 year of Triac treatment.
Results: Currently, all patients (age: 166 year) have been enrolled of which 35 completed 1 year of follow-up. Triac treatment effectively reduced serum TSH concentrations (mean ± S.D.: 2.9±1.6 to 1.0±1.0 mU/l; P<0.001), resulting in a strong reduction of T3 concentrations (5.2±1.4 to 1.8±0.8 nmol/l; P<0.001), when comparing baseline and end-study measurements in these 35 patients. Importantly, the age-specific S.D. scores for BW (−3.1±1.9 to −2.7±1.8, P<0.05) and BMI (−2.8±2.6 to −2.2±2.6, P<0.05) significantly increased, whereas basal HR (102±13 to 93±8 bpm, P<0.01) significantly decreased. Moreover, serum markers that reflect tissue thyroid state improved such as SHBG (222±88 to 186±76 nmol/l, P<0.005) and Creatinine (31.5±10.3 to 36.1±13.0 μmol/l, P<0.005). The youngest patients had some improvement in neuropsychological markers. No (severe) adverse reactions to Triac occurred.
Conclusions: This interim analysis indicates that Triac treatment effectively normalizes serum T3 concentrations in patients with MCT8 deficiency. Both clinical outcomes (BW, BMI and HR) and biochemical markers representing thyroid state in different tissues improved on Triac treatment. Future studies should aim to evaluate the effect of Triac on the neurocognitive phenotype once treatment is installed early after birth.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology